Neurogenic inflammation contributes to many clinically relevant states, including arthritis, inflammatory bowel disease, chronic bronchitis, migraine and interstitial cystitis. Such a type of inflammation has been known to be initiated by release of inflammatory substances from sensory nerve terminals by which painful sensation may be caused and even exacerbated. In order to investigate its mechanisms, we have experimentally established an acute model of neurogenic inflammation by using an intradermal capsaicin (CAP) injection. The long-term goal of the proposed studies is to elucidate how neurogenic inflammation is initiated by activation of transient receptor potential vanilloid-1 (TRPVO receptors, then maintained by triggering the centrally mediated antidromic activity, dorsal root reflexes (DRRs) to exacerbate inflammatory pain, and how sympathetic-sensory interactions modulate the neurogenic inflammation. Uncovering these mechanisms will lead to improvements in anti-inflammatory therapies. The overall hypothesis of the present proposal is that activation of TRPV-i receptors either by intradermal injection of CAP or tissue injury initiates neurogenic inflammation that will then be maintained and develops by triggering DRRs. Sympathetic-sensory interactions modulate the neurogenic inflammation by regulating the functional activity of TRPVi receptors via activating signal transduction cascades, such as protein kinase C (PKC). Specific Aim 1 is to determine if neurogenic inflammation following CAP injection involves triggering DRRs that cause the release of calcitonin gene-related peptide and/or substance P from primary afferent nociceptors and if this process would in turn enhance the CAP-induced sensitization of primary afferent nociceptors, as well as analyze if this process is initiated by activation of TRPN/! receptors. Specific Aim 2 is to examine if activation of the PX/! receptors in primary afferent nociceptors plays an important role in enhancing DRRs by activating GABAergic interneurons in dorsal horn circuits. Specific Aim 3 is to determine if phosphorylation of PKC takes place in the primary afferent neurons when neurogenic inflammation is initiated and develops, and if TRPN/T receptors are up-regulated by the phosphorylation of PKC. Specific Aim 4 is to examine if sympathetic effects on neurogenic inflammation by release of norepinephrine and adenosine 5'-triphosphate are done by modulating the function of TRPNA, receptors via the PKC cascade. The experimental approaches that will be used include electrophysiological recordings and pharmacological modulation of proteins involved in nociceptive signal transduction, blood flow and paw-thickness measurements to reflect neurogenic inflammation induced by CAP injection, and immunohistochemical and Western blotting studies to analyze changes in the expression of phosphorylated receptors and PKC before and after CAP injection.